Age-associated callus senescent cells produce TGF- <b>β</b>1 that inhibits fracture healing in aged mice

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Abstract

Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF- β1. TGF- β–neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF- β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF- β1 signaling is a molecular mechanism for fractures in the elderly via SCs.

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Cellular Senescence: Defining a Path Forward

Vassilis G. Gorgoulis, Peter Adams, Andrea Alimonti … (2019)

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.

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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Wen Xue, Lars Zender, Cornelius Miething … (2007)

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

Darren J. Baker, Tobias Wijshake, Tamar Tchkonia … (2012)

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

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Author and article information

Contributors

Jiatong Liu

Jun Zhang

Xi Lin:

ORCID: http://orcid.org/0000-0001-5905-5311

Brendan F. Boyce:

ORCID: http://orcid.org/0000-0002-3587-4854

Hengwei Zhang:

ORCID: http://orcid.org/0000-0001-5355-7257

Lianping Xing

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J Clin Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 15 April 2022

Publication date (Electronic, collection): 15 April 2022

Publication date (Print, pub): 15 April 2022

Publication date PMC-release: 15 April 2022

Volume: 132

Issue: 8

Electronic Location Identifier: e148073

Affiliations

[1 ]Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, USA.

[2 ]Plastic Surgery Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China.

[3 ]Suzhou Institute of Systems Medicine, Suzhou, China.

Author notes

Address correspondence to: Lianping Xing or Hengwei Zhang, Department of Pathology and Laboratory Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. Phone 585.273.4090; Email: lianping_xing@ 123456urmc.rochester.edu (LX); 585.276.7127; Email: hengwei_zhang@ 123456urmc.rochester.edu (HZ).

Authorship note: JL and JZ are co–first authors and contributed equally to this work. HZ and LX are co–corresponding authors.

Author information

Xi Lin http://orcid.org/0000-0001-5905-5311

Brendan F. Boyce http://orcid.org/0000-0002-3587-4854

Hengwei Zhang http://orcid.org/0000-0001-5355-7257

Article

Publisher ID: 148073

DOI: 10.1172/JCI148073

PMC ID: 9012290

PubMed ID: 35426372

SO-VID: 0e9300a6-e0ef-475d-a4cd-1f0ee997b285

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 March 2021

Date accepted : 16 February 2022

Funding

Funded by: NIH Office of the Director, https://doi.org/10.13039/100000052;

Award ID: AG059775

Funded by: NIH Office of the Director, https://doi.org/10.13039/100000052;

Award ID: AG049994

Funded by: NIH Office of the Director, https://doi.org/10.13039/100000052;

Award ID: AR069789

Funded by: NIH Office of the Director, https://doi.org/10.13039/100000052;

Award ID: P30AR061307,AR069655

Funded by: National Natural Science Foundation of China, https://doi.org/10.13039/501100001809;

Age-associated callus senescent cells produce TGF- β1 that inhibits fracture healing in aged mice

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Fracture and Structural Integrity

Most cited references 75

Cellular Senescence: Defining a Path Forward

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

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